Normal vaginal flora is reported to be composed predominantly of Lactobacillus species, with an average pH of about 4.0. This low pH is reported to foster growth and maintenance of the acidophilic Lactobacilli that dominate the normal flora.
Metronidazole is an antibacterial compound that has been used to treat various microbial diseases, including bacterial vaginosis (BV). Metronidazole has been reported to be effective in treating BV when administered orally. For example, as of 1985, the Center for Disease Control recommended an oral dose of 500 mg of metronidazole twice daily for seven days.
MetroGel-Vaginal® (3M, St. Paul, Minn.) is a product containing 0.75% metronidazole, methylparaben, propylparaben, edetate disodium, Carbomer 934P, propylene glycol, water, and sodium hydroxide to pH 4.0. The Food and Drug Administration's Approved Drug Products and Therapeutic Equivalents (The “Orange Book”) lists, for MetroGel-Vaginal®, U.S. Pat. No. 5,536,743 (“the '743 patent”), Pat. No. 5,536,744 (“the '744 patent”), and Pat. No. 4,837,378 (“the '378 patent”).
The '743 and the '744 patents describe compositions and methods directed to the treatment of bacterial vaginosis. These patents describe metronidazole in a buffered, non-flowing pharmaceutical composition having a pH value below 4.25. These patents repeatedly emphasize the criticality of the low pH of the composition. For instance, in Example 12 in each of these two patents, the clinical cure rate of MetroGel-Vaginal® (pH 4) was found to be superior to the same composition at pH 6. The conclusion was that these results “underscore clearly the advantage of the relatively lower pH value for the vaginal preparation.”
The '378 patent is directed to aqueous metronidazole gels containing water-dispersible polycarboxylated vinyl polymers (such as Carbopol® (Noveon Pharmaceuticals, Cleveland, Ohio)) for the treatment of skin disorders.
U.S. Pat. No. 6,348,203 (“the '203 patent”) is directed toward imidazole derivatives that can be used in the topical treatment of certain dermatological diseases. The '203 patent discloses compositions that are specially formulated and buffered to a pH that is within the physiologically tolerable range for dry or inflamed skin. The '203 patent, however, does not teach or suggest whether the disclosed compositions could be suitable for applying to vaginal tissue for treatment or prevention of vaginal diseases, let alone the appropriate dosage for vaginal treatment.
Romanian Patent No. 80,363, published Nov. 30, 1982, describes a vaginal gel containing antifungal, antiparasitic, and large amounts of antibacterial agents (such as metronidazole) in a Carbopol® 940 base.
Flagyl® (G.D. Searle & Co., Skokie, Ill.) is a pharmaceutical product that has been approved in Canada. In one form, it is a high-dose (500 mg) vaginal cream containing 10% metronidazole, glycerin, glyceryl monostearate, methylparaben, propylparaben, purified water, stearic acid, and triethanolamine for the treatment of trichomoniasis.